Crizotinib Induces Dramatic Response in ALK-Positive Lymphoma

Roxanne Nelson

December 11, 2010

December 11, 2010 (Orlando, Florida) — Crizotinib, an investigational first-in-class compound that inhibits the anaplastic lymphoma kinase (ALK), has demonstrated impressive results in a small group of patients with relapsed anaplastic large cell lymphoma (ALCL).

Four ALK+ ALCL patients who had developed resistance to cytotoxic therapy were treated with crizotinib (Pfizer) as part of a compassionate use named patient protocol. "We have now treated the first 4 patients with ALK-positive lymphoma," said Carlo B. Gambacorti-Passerini, MD, who presented the case studies of 2 of the patients at a poster presentation here during the American Society of Hematology 52nd Annual Meeting.

"We have observed dramatic clinical activity in the sense that the patient got subjectively better in terms of fever and pain within a few days of treatment," explained Dr. Gambacorti-Passerini, professor of internal medicine at the University of Milan Bicocca and director of the Clinical Research Unit at S. Gerardo Hospital, in Monza, Italy. "We then confirmed this activity with [positron emission tomography (PET)] and [computed tomography (CT)] scans as early as 2 weeks after beginning treatment."

ALCL is a rare and aggressive type of t-cell lymphoma. "Patients are usually sensitive to chemotherapy, as in any type of lymphoma in general," Dr. Gambacorti-Passerini told Medscape Medical News. "But once they relapse, the options are almost nonexistent."

Unfortunately, these patients have a very low life expectancy, he added. "The disease is very aggressive."

In this case, Dr. Gambacorti-Passerini pointed out, the presence of ALK rendered the treatment as "targetable," in which a specific approach could be used, rather than chemotherapy. Deregulated ALK tyrosine kinase activity represents the driver alteration in ALCL via the phosphorylation of proteins belonging to signal transduction pathways involved in cellular proliferation, apoptosis, and differentiation.

Three of the 4 patients are currently in complete remission, said Dr. Gambacorti-Passerini. "One patient has been on treatment for 6 months, and the second patient has been on treatment for 5 months," he said. "The remaining 2 patients have only had a short duration of treatment."

Impressive Results in Lung Cancer

Crizotinib has thus far only been evaluated for non-small cell lung cancer (NSCLC). "But because of the presence of the translocation that fuses and deregulates ALK, we had strong rationale for convincing Pfizer to let us [use] it under our compassionate program, even if there was no patient with this disease that had ever been treated with this drug," he said.

Early-phase studies of crizotinib in NSCLC have shown great promise and generated a wave of excitement. In an expanded cohort study instituted after a phase 1 dose escalation trial, treatment with crizotinib resulted in an overall response rate of 57% in patients with advanced ALK-positive NSCLC (N Engl J Med. 2010;363:1693-1703).

In the results of a phase 2 clinical trial, which were reported during a plenary session at the American Society of Clinical Oncology 2010 Annual Meeting, crizotinib treatment showed an objective response rate of 57% and a disease control rate of 87% in patients with ALK-positive NSCLC.

Case Studies

The first patient is a 26-year-old woman who had received 7 cycles of CHOP-15 and achieved a partial response that lasted only 1 month. She was subsequently treated with DHAP (dexamethasone, high dose Ara-C, cisplatin) and ICE (ifosfamide, carboplatin, etoposide) in an attempt to collect stem cells for an autologous bone marrow transplant.

Despite these 2 salvage regimens, she suffered a relapse only 2 to 3 weeks following each treatment. Before receiving crizotinib, the patient had a fever, cervical and inguinal adenopathies, and positive PET and CT scans of para-aortic and iliac adenopathies.

After treatment with crizotinib, the fever subsided within 48 hours, and by day 7, all of the superficial adenopathies were no longer present. Her PET and CT scans and bone marrow aspirate, which were performed at day 28, showed a complete regression of lesions that has persisted for 6 months posttreatment. Adverse events included transient ocular flashes and grade I liver function test elevation.

The second patient is a 21-year-old man who was diagnosed with ALK-positive ALCL in August 2009. He received 6 cycles of CHOP therapy, achieving a complete remission that ended in February 2010. The patient underwent reinduction/mobilization chemotherapy with a regimen of MAD (mitoxantrone, cytarabine dexamethasone) and received an autologous bone marrow transplantation in May 2010 after conditioning with a regimen of BEAM (carmustine, etoposide, cytarabine, melphalan).

He obtained a partial response that lasted only 1 month. Before receiving crizotninb, the patient's signs/symptoms included fever, axillary and inguinal adenopathies, and positive PET and CT scans of all internal nodal stations. Within 8 days of beginning treatment, symptoms and all superficial adenopathies disappeared, and at 12 days, a PET scan showed complete regression of all lesions.

Thus far, reported adverse events include grade I dizziness; the patient is currently in his fifth month of treatment.

Even though the clinical activity is impressive, Dr. Gambacorti-Passerini cautioned that the number of patients is limited and the follow-up is very short term. "All of them were terminal patients, so I cannot say anything about the duration of this response," he said. "But I can say that the clinical activity is definitely there."

He noted that he and his colleagues will soon be starting a phase 1B study with crizotinib in this population. "We plan to enroll 40 patients in 7 centers in Italy," he said. "This is definitely a therapeutic option because once the disease relapses, there are no options."

The authors have disclosed no relevant financial relationships.

American Society of Hematology 52nd Annual Meeting: Abstract 2877. Presented December 6, 2010.

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